The use of theranostic gadolinium-based nanoprobes to improve radiotherapy efficacy

Abstract

A new efficient type of gadolinium-based theranostic agent (AGuIX®) has recently been developed for MRI-guided radiotherapy (RT). These new particles consist of a polysiloxane network surrounded by a number of gadolinium chelates, usually 10. Owing to their small size (<5 nm), AGuIX typically exhibit biodistributions that are almost ideal for diagnostic and therapeutic purposes. For example, although a significant proportion of these particles accumulate in tumours, the remainder is rapidly eliminated by the renal route. In addition, in the absence of irradiation, the nanoparticles are well tolerated even at very high dose (10 times more than the dose used for mouse treatment). AGuIX particles have been proven to act as efficient radiosensitizers in a large variety of experimental in vitro scenarios, including different radioresistant cell lines, irradiation energies and radiation sources (sensitizing enhancement ratio ranging from 1.1 to 2.5). Pre-clinical studies have also demonstrated the impact of these particles on different heterotopic and orthotopic tumours, with both intratumoural or intravenous injection routes. A significant therapeutical effect has been observed in all contexts. Furthermore, MRI monitoring was proven to efficiently aid in determining a RT protocol and assessing tumour evolution following treatment. The usual theoretical models, based on energy attenuation and macroscopic dose enhancement, cannot account for all the results that have been obtained. Only theoretical models, which take into account the Auger electron cascades that occur between the different atoms constituting the particle and the related high radical concentrations in the vicinity of the particle, provide an explanation for the complex cell damage and death observed.

68 Ga-Radiolabeled AGuIX Nanoparticles as Dual-Modality Imaging Agents for PET/MRI-Guided Radiation Therapy

“…For in vivo application in mice, it was proven that after bolus injection of these NPs, no toxicity effects were shown at doses up to ten-times higher than the ther- apeutic dose, which corresponds to an injection of 8 μmol of [Gd 3+ ]. Furthermore, no significant difference in creatinine levels between AGuIX and control groups was recorded, suggesting the absence of any significant nephrotoxicity related to AGuIX NPs [9].…”

“…The design of the AGuIX NPs has been made in order to ensure a fast and exclusive renal elimination and to avoid toxicity concerns [9,12,21,22]. The present work was designed to assess the passive accumulation of 68 GaAGuIX@NODAGA in a U87MG tumor model, both by ex vivo biodistribution studies and in vivo PET and MR imaging studies.…”

“…Thanks to their radiosensitizing properties, AGuIX NPs have proven to be an excellent tool for radiation therapy, and recent literature shows how MRI can be used to perform imageguided radiation therapy with them [7,[9][10][11][12]. However, a dual-modality PET/MRI imaging agent which combines the advantages of both imaging modalities has more to offer than a single-modality, gadolinium MR imaging agent, in this case, and can be used as a companion diagnostic agent.…”

Radiosensitizing Effect of TRPV1 Channel Inhibitors in Cancer Cells

“…17,29) Gadolinium, hydrogen peroxide, and tirapazamine have also been investigated as radiosensitizers, but have various disadvantages. [30][31][32] Based on our finding that activation of the TRPV1 channel promotes the repair response to DNA damage, 20) we speculated that inhibitors of this channel might be available as novel radiosensitizers. Although the mechanism of TRPV1 channel activation after irradiation is still unknown, possible mediators include radiation-induced reactive oxygen species and secondary generation of nitric oxide in irradiated cells, 33) or radiation-induced extracellular release of ATP from cells, we have reported.…”

Improving proton therapy by metal-containing nanoparticles: nanoscale insights

“…[11][12][13][14] Furthermore, nanostructures were found to not only amplify radiation effects, but also improve in situ tumor diagnostics. In particular, gadolinium-based NPs (GdBNs) are magnetic resonance imaging active agents for which amplification of cell killing was observed using high-energy photons [15][16][17] and carbon ions as incident radiation. 18 The new properties of these multimodal compounds open up promising perspectives to implement theranostics (therapy and diagnosis based on a single compound) in radiation-based cancer therapy.…”